Functions of transforming growth factor-beta family type I receptors and Smad proteins in the hypertrophic maturation and osteoblastic differentiation of chondrocytes
2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 37, 33545-33558 p.Article in journal (Refereed) Published
We investigated the effects of bone morphogenetic protein (BMP)-2, a member of the transforming growth factor-beta superfamily, on the regulation of the chondrocyte phenotype, and we identified signaling molecules involved in this regulation. BMP-2 triggers three concomitant responses in mouse primary chondrocytes and chondrocytic MC615 cells. First, BMP-2 stimulates expression or synthesis of type II collagen. Second, BMP-2 induces expression of molecular markers characteristic of pre- and hypertrophic chondrocytes, such as Indian hedgehog, parathyroid hormone/parathyroid hormone-related peptide receptor, type X collagen, and alkaline phosphatase. Third, BMP-2 induces osteocalcin expression, a specific trait of osteoblasts. Constitutively active forms of transforming growth factor-beta family type I receptors and Smad proteins were overexpressed to address their role in this process. Activin receptor-like kinase (ALK)-1, ALK-2, ALK-3, and ALK-6 were able to reproduce the hypertrophic maturation of chondrocytes induced by BMP-2. In addition, ALK-2 mimicked further the osteoblastic differentiation of chondrocytes induced by BMP-2. In the presence of BMP-2, Smad1, Smad5, and Smad8 potentiated the hypertrophic maturation of chondrocytes, but failed to induce osteocalcin expression. Smad6 and Smad7 impaired chondrocytic expression and osteoblastic differentiation induced by BMP-2. Thus, our results indicate that Smad-mediated pathways are essential for the regulation of the different steps of chondrocyte and osteoblast differentiation and suggest that additional Smad-independent pathways might be activated by ALK-2.
Place, publisher, year, edition, pages
2002. Vol. 277, no 37, 33545-33558 p.
Activin Receptors; Type I/*physiology, Animals, Bone Morphogenetic Proteins/pharmacology, Cell Differentiation, Cell Line, Chondrocytes/drug effects/*physiology, Collagen Type II/genetics, DNA-Binding Proteins/*physiology, Humans, Hypertrophy, Mice, Osteoblasts/drug effects/*physiology, Proteins, Receptors; Transforming Growth Factor beta/*physiology, Smad Proteins, Smad1 Protein, Trans-Activators/*physiology, Transforming Growth Factor beta
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-10464DOI: 10.1074/jbc.M202086200PubMedID: 12082094OAI: oai:DiVA.org:uu-10464DiVA: diva2:38232